This Project follows the central theme of this Center proposal in refining existing and developing new fMRI techniques capable of investigating cognitive function. It utilizes the entire range of resources and expertise of the Center by customizing each aspect of the fMRI experiment including instrumentation, acquisition software and signal processing. Other Projects use Bold contrast fMRI to probe cognitive processing in normal subjects with the underlying reasonable assumption that changes in Bold contrast reflect changes in neuronal activity in a monotonically increasing manner. The nature of the Bold contrast response is complex. This Project develops methods of arterial water labeling (AWL) and tissue lactate imaging (TlacC) to provide alternative and possibly quantitative probes of neuronal activity. AWL is a potentially quantitative non-invasive measure of resting regional brain perfusion that is to be calibrated against regional CBF as measured by PET. If quantitative AWL can be developed to measure resting state and changes in perfusion, a potential confounding source of differences in Bold responses among normal individuals can be measured and therefore controlled. Lactate imaging is a significant challenge in all aspects of non-water MRI but is now within reach and provides a probe metabolically close to neuronal activity. This approach has required single stimulus synchronization strategies to be developed. TlacC, based on transient changes in tissue lactate content due to neuronal activity, avoids the complexities of interpreting the downstream and slower hemodynamic responses of Bold. This Project interacts with a Core in applying stimulus-synchronized image acquisition to investigate single stimulus responses at high temporal resolution using the Bold and TlacC methods. Simple paradigms are to be used before moving to the other Projects with more complex paradigms. Focused effort on technological advancement of alternatives to Bold contrast and enhancement of the temporal response of fMRI are ideally suited to the uniquely equipped MR Research Center.